The objective of this proposal is to advance studies recently initiated dealing with hormonal action on the heart and coronary circulation in the newborn and young mammal. Our lamb model permits simultaneous evaluation of cardiac performance, myocardial oxygen and substrate metabolism, and coronary flow patterns in a preparation with functional autonomic and hormonal systems. We plan to focus on insulin, its modes of action reflected by changes in cardiac function and metabolism, and its interrelationships with the catecholamines and possible effects on neurotransmitter function. Our studies have demonstrated a signficant interplay between these hormones in which effects on calcium movements probably represent the final common pathway. The potential role of the adenylate cyclase system will also be assessed. In preliminary studies we have found that alloxan diabetes can be produced consistently in the lamb and manipulated to yield an acute or chronic diabetic state, with or without ketoacidosis. These preparations represent a model for juvenile diabetes mellitus. The effects of insulin deficiency and insulin administration on cardiovascular function, metabolism and autonomic regulatory systems will be studied. Changes associated with acidosis will be defined. We have shown that alpha adrenergic control of the coronary circulation is operative in the newborn, but is dependent upon adrenal function. We will attempt to identify the adrenal factor, which may be cortical or medullary, We have also found in preliminary studies that insulin administration produces coronary dilatation. Changes in autonomic sensitivity, and responsiveness to hypoxia and acidosis will be tested to explain these findings. Isolated cardiac muscle preparations will be used to study intrinsic myocardial receptor and contractile properties of insulin and the effects of pH and ionic shifts.